Congestive heart failure (CHF) is a pathophysiological state in which the heart is unable to pump sufficient blood to meet the metabolic needs of the body. The underlying basis of this disorder is a deficiency of myocardial contractility, resulting in a decreased mechanical ability to pump blood and in turn, a decreased cardiac output. Congestive heart failure may result from a number of factors affecting the myocardium, altering systolic and/or diastolic function. As the condition progresses, activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system lead to an increase in the total peripheral resistance. In addition, elevated levels of arginine vasopressin (AVP) have been reported in some patients with heart failure, although its pathophysiologic role is unknown. It has been postulated that the increase in AVP may provide increased systemic vascular resistance and impaired water excretion as a compensatory mechanism to the low cardiac output associated with CHF.
Arginine vasopressin, also known as antidiuretic hormone (ADH), is synthesized in the magnocellular neurosecretory cells of the paraventricular and supraoptic nuclei of the hypothalamus and stored in the posterior pituitary. There are 2 classes of AVP receptors, V1 and V2. There are 2 subclasses of V1 receptors, V1A and V1B. V1A receptors are found in the vasculature, and mediate the pressor response of AVP by increasing the contraction of blood vessels. V1A receptors are also found on platelets, where they mediate platelet aggregation. V1B receptors are located in the anterior pituitary, and mediate adrenocorticotropic hormone (ACTH) release. V2 receptors are located in the collecting ducts of the kidney; they are coupled to aquaporine channels and modulate free water clearance. Arginine vasopressin is released into the circulation in response to an increase in plasma osmolality (mediated by osmoreceptors) or a decrease in plasma volume or blood pressure (mediated by baroceptors). However, there are other stimuli for AVP release, including norepinephrine, angiotensin II, emotion, nausea and vomiting, and fever.
Heart failure is characterized by increased sympathetic nervous system activity and changes in several neurohormonal factors, such as angiotensin II, aldosterone, endothelin-1, and atrial natriuretic factor. In patients with advanced CHF, plasma levels of AVP are also increased. While the mechanism of AVP release in CHF is not well-understood, infusion of AVP into CHF patients results in an increase in systemic vascular resistance and a redistribution of cardiac output. These observations suggest that the increased levels of AVP observed in patients with severe CHF play a role in the pathogenesis of this disease. Several compounds are known which antagonize the hormonal effects of AVP, for example, the benzazepines disclosed in U.S. Pat. No. 5,723,606.
The cardiac dysfunction underlying CHF results in a decreased effective tissue perfusion, which in turn stimulates the renin-angiotensin-aldosterone and sympathetic nervous systems to promote Na+ retention by the kidney, which can result in the formation of edema. Patients with CHF and evidence of pulmonary congestion or peripheral edema are routinely treated with diuretics. Thiazide diuretics, which act on the distal convoluted tubule of the kidney by inhibiting the Na+—Cl− cotransporter, may initially be employed. However, they produce only a slight increase (5%–8%) in the amount of sodium excretion by the kidney, and subject the patient to risk of hypokalemia (low blood potassium) and hyponatremia. In patients with more advanced heart failure and signs of extracellular fluid accumulation, loop diuretics are generally used. Loop diuretics, such as furosemide, act at the thick ascending limb of the loop of Henle by competing for the Cl− site on the Na+—K+—Cl− transporter. These diuretics are capable of increasing the fractional sodium excretion to more than 20% of the filtered load, albeit at an even greater risk of potassium wasting in the urine and hypokalemia and hyponatremia in the serum.
We have now discovered that the use of diuretics in combination with compounds which inhibit vasopressin enzymes is surprisingly effective in promoting increased clearance of fluid by the kidney, and decreased excretion of sodium and potassium in the urine, thereby minimizing the risk of electrolyte disturbance such as hypokalemia and hyponatremia. An object of this invention is thus to provide compositions comprising a vasopressin antagonist in combination with a loop diuretic agent, and a method for treating edematous conditions such as CHF using such compositions.